Effect of Antifungal Drugs on Cytochrome P450 (CYP) 1A2, CYP2D6, and CYP2E1 Activities in Human Liver Microsomes

Abstract

Antifungal drugs, including fluconazole, itraconazole, micafungin, miconazole, and voriconazole, are widely used in the treatment of systemic candidal infections and mycoses. The mechanism of action of these antifungal drugs except for micafungin is the inhibition of fungal cytochrome P450 (CYP, 14a-sterol demethylase), an enzyme responsible for the conversion of lanosterol to 14a-demethyllanosterol in the ergosterol biosynthetic pathway, 1,2) whereas micafungin inhibits 1,3-b-D-glucan synthase, leading to disruption of growing fungal cell wall and death of the fungal cell. 3,4)Multiple drug therapy is a common therapeutic practice, particularly in patients with several diseases or conditions, and many drug-drug interactions involving metabolic inhibition are being reported. 5,6) Recently, we have demonstrated that itraconazole and miconazole, as well as ketoconazole, had higher inhibitory effects on CYP3A4 metabolic activities than fluconazole and micafungin.7) In addition, the K i values of fluconazole and micafungin against nifedipine oxidation activity, a marker enzyme activity of CYP3A4, have been reported to be 10.7 mM and 17.3 mM, respectively. 8) Zhang et al. 9) reported that miconazole inhibits several CYPs, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, with K i values ranging from 0.01 to 7.3 mM. Furthermore, it is likely that fluconazole and voriconazole inhibit CYP2C9, CYP2C19, and CYP3A4.2,10-13) On the other hand, fluconazole and itraconazole are reported to exhibit no inhibition of CYP2E1, whereas the K i value of miconazole against CYP2E1 activity is 4 mM. 14) However, there are few studies comparing the effect of antifungal drugs on the drugmetabolizing activity by human hepatic CYPs, such as CYP1A2, CYP2D6, and CYP2E1, under the same experimental conditions.Many inhibitors are known to be activated metabolically to a reactive intermediate(s) that, in turn, is irreversibly or quasi-irreversibly bound to the enzyme(s).15) For example, some acetylenes, including those synthetic steroids such as gestodene and ethinyl estradiol, cause mechanism-based inactivation of CYP3A4.16) Sorivudine is converted by gut flora to (E)-5-(2-bromovinyl)uracil (BVU), which is metabolized to dihydro-BVU by dihydropyrimidine dehydrogenase (DPD), and the dihydro-BVU binds to DPD itself.17) Numerous laboratories have indicated that these mechanism-based inactivators exhibit preincubation time-dependence of inhibition. [16][17][18][19][20][21][22][23][24][25][26][27] In the present study, we compared the effects of five antifungal drugs on specific activities by CYP1A2, CYP2D6, and CYP2E1 in human liver microsomes under the same experimental conditions. In addition, the effect of preincubation was estimated in order to investigate whether these antifungal drugs are the mechanism-based inhibitors. ) and itraconazole from Janssen-Kyowa (Tokyo, Japan). 7-Ethoxyresorufin, resorufin, debrisoquine sulfate, and chlorzoxazone were obtained from Sigma Chemical Co. (St. Louis, MO, U.S.A.). 4-Hydroxydebrisoquine ...

Fetal Serotonin Reuptake Inhibitor Antidepressant Exposure: Maternal and Fetal Factors

“…44 Interactions may also unexpectedly occur among commonly prescribed, as well as OTC, medications during pregnancy. Yeast infections are treated with fluconazole and miconazole, which inhibit key CYP enzymes involved with 45 Such interactions may increase maternal plasma levels, potentially also affecting fetal plasma concentrations, and the risk of drug-elicited adverse effects, with consequences for fetal cardiovascular, neurologic, endocrine, or metabolic function.…”

Oral voriconazole and miconazole oral gel produce comparable effects on the pharmacokinetics and pharmacodynamics of etoricoxib

“…This reaction is mainly catalyzed by CYP3A (60%), but the rest is catalyzed equally between CYP2C9, CYP2C19, CYP2D6, and CYP1A2 [2,3]. Correspondingly, previous in vitro studies have indicated that miconazole is a nonselective inhibitor of several CYPs, namely CYP3A, 2C9, 2C19, 1A2, 2A6, and 2B6 [4][5][6]. In our study, after 3-day pretreatment with miconazole oral gel (3.5 ml ≈ 85 mg three times daily), miconazole plasma concentrations were quantifiable (4 ng/ml or more, data not shown) up to 24 h after the last dose and were sufficient to cause similar increase in the concentrations of etoricoxib than systemic oral voriconazole.…”

“…Timed blood samples were drawn immediately before and at 0.5, 1, 1.5, 2, 2.5, 3,4,5,6,8,12,24,48, and 72 h after etoricoxib administration. After 12 h, blood samples were drawn by venipuncture.…”

“…Nowadays, miconazole is almost solely used as a topical preparation, e.g., as an oral gel for treating oral fungal infections. In vitro, miconazole inhibits many CYPs, namely, CYP3A, CYP2C9, CYP2C19, CYP1A2, CYP2A6, CYP2B6, and CYP2D6 [4][5][6], and in vivo the interaction between systemically administered miconazole and the CYP2C9 substrate, warfarin, is well established [7]. Topically applied miconazole, such as oral gel, is generally considered a safer treatment with regard to drug interactions, because only small amount of miconazole is absorbed after miconazole oral gel application.…”

Systemic uptake of miconazole during vaginal suppository use and effect on CYP1A2 and CYP3A4 associated enzyme activities in women

“…Miconazole has been reported to inhibit several CYP-enzymes in human liver or lymphoblast microsomes in vitro, including CYP1A2 and CYP3A4, with an inhibition constant (K i ) of 3.2 and 0.028 µM [14] and a half maximal inhibitory concentration (IC 50 ) of 2.9 and 0.074 µM [41,42], respectively. This indicates, that miconazole in the mean absorbed concentration of 12.9 µg/L serum corresponding to 0.03 µM could have an effect on the enzymes in vivo also.…”